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Alpha-Lipoic Acid Monograph α - Lipoic Acid S S CH2 CH2 CH2 CH2 CH2 CH2 COOH CH2 Dihydrolipoic Acid SH SH CH2 CH2 CH2 Alpha-lipoic Acid CH2 Introduction Alpha-lipoic acid (ALA – also known as thioctic acid) was discovered in 1951 as a molecule that assists in acyl-group transfer and as a coenzyme in the Krebs cycle. In the 1980s, the scientific community realized alpha-lipoic acid is a powerful antioxidant. Several qualities distinguish alpha-lipoic acid from other antioxidants: ALA can be synthesized by animals and humans;1 it neutralizes free radicals in both the fatty and watery regions of cells, in contrast to vitamin C (water soluble) and vitamin E (fat soluble); and, ALA functions as an antioxidant in both its reduced and oxidized forms.2 CH2 CH2 CH2 COOH Pharmacokinetics ALA appears to be readily absorbed from an oral dose and converts easily to its reduced form, dihydrolipoic acid (DHLA), in many tissues of the body.3 The effects of ALA and DHLA are present both intra- and extracellularly. ALA contains an asymmetrical carbon and thus has two possible optical isomers. These are designated as R-lipoic acid (R-ALA) and S-lipoic acid (S-ALA). Naturally occurring ALA is in the R configuration, bound to a protein where it functions as an essential cofactor for several mitochondrial enzyme complexes involved in energy production and the catabolism of alpha-keto acids and amino acids.4 Nutritional supplements of ALA are typically comprised either of R-ALA alone or a racemic mixture of R-ALA and S-ALA (RS-ALA). Human studies using oral racemic mixtures of ALA have observed plasma concentrations of R-ALA to be greater than that of S-ALA.5,6 One study found that, following oral administration of 50- or 600-mg racemic mixture of lipoic acid, maximum plasma concentrations (Cmax) of R-ALA were double that of S-ALA (following 50-mg dose: 135.45 ng/mL and 67.83 ng/mL, respectively; following 600-mg dose: 1,812.32 ng/mL and 978.20 ng/mL, respectively).6 Mechanisms of Action Alpha-lipoic acid is a potent antioxidant in both fat- and water-soluble mediums. Furthermore, its antioxidant activity extends to both its oxidized and reduced forms. DHLA is capable of directly regenerating ascorbic acid from dehydroascorbic acid and indirectly regenerating vitamin E.7 Researchers have also found ALA increases intracellular glutathione8 and coenzyme Q109 levels. Alpha-lipoic acid appears capable of chelating certain metals. It forms stable complexes with copper, manganese, and zinc.10 In animal studies, it has been found to protect against arsenic poisoning,11 and, in both animal and in vitro studies, ALA reduced cadmium-induced hepatotoxicity.12 In vitro, ALA chelated mercury from renal slices.13 Page 232 Alternative Medicine Review u Volume 11, Number 3 u 2006 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006 Alpha-Lipoic Acid Monograph Mechanisms that may account for lipoic acid’s benefit in preventing diabetic complications include prevention of protein glycosylation14 and inhibition of the enzyme aldose reductase, the latter of which subsequently inhibits conversion of glucose and galactose to sorbitol.15,16 Accumulation of sorbitol has been implicated in the pathogenesis of various diabetic complications, including “sugar cataracts” where sorbitol accumulates in the lens. Clinical Indications Diabetes Lipoic acid has the potential to prevent diabetes (at least in animals), influence glucose control, and prevent chronic hyperglycemia-associated complications such as neuropathy. Blood-sugar Management/Insulin Sensitivity Acting as a potent antioxidant, DHLA protected rat pancreatic islet cells from destruction by reactive oxygen species.17 In vitro, lipoic acid stimulated glucose uptake by muscle cells in a manner similar to insulin.18 Type 2 diabetics given 1,000 mg lipoic acid intravenously (IV) experienced a 50-percent improvement in insulin-stimulated glucose uptake.19 In an uncontrolled pilot study, 20 type 2 diabetics were given 500 mg lipoic acid IV for 10 days. While there was an average 30-percent increased uptake of glucose, there were no changes in fasting blood sugar or insulin levels.20 In a study examining the effect of lipoic acid as a co-factor of the pyruvate dehydrogenase complex on both lean and obese type 2 diabetics, insulin sensitivity, glucose effectiveness, serum lactate levels, and pyruvate levels were tested after oral glucose tolerance load. Treatment with 600 mg ALA twice daily for four weeks increased insulin sensitivity and prevented serum lactate/pyruvate-induced hyperglycemia.21 In a placebo-controlled, multi-center pilot study, 74 patients with type 2 diabetes were randomized to receive 600 mg ALA or placebo orally once, twice, or three times daily, for four weeks. Although no significant differences regarding the various doses of ALA were observed, at the end of the trial it was found that patients who received ALA experienced significant improvement in insulin-stimulated glucose disposal compared to those on placebo (+27%; p<0.01). This suggests oral administration of ALA can improve insulin sensitivity in type 2 diabetics.22 Experimental research indicates R-ALA may be more effective than S-ALA in improving insulin sensitivity. In an animal model of non-diabetic insulin resistance, R-ALA for 10 days increased glucose uptake by skeletal muscle of obese rats by 65 percent, compared to 29 percent with S-ALA. In addition, RALA significantly reduced plasma insulin by 17 percent; whereas, S-ALA increased insulin levels by 15 percent. This seems to indicate an increase in insulin resistance with S-ALA.23 Diabetic Nephropathy One animal study suggested that ALA may be effective in the prevention of early diabetic glomerular injury and may provide more protection than high doses of vitamin C or vitamin E.24 The study observed ALA (30 mg/kg body weight daily for two months) given to diabetic rats either prevented or significantly attenuated increases in urinary albumin excretion, fractional albumin clearance, glomerular volume, and glomerular content of immunoreactive transforming growth factor-ß and collagen α1 to levels no different from non-diabetic controls. In addition, it was found that ALA, but not vitamins C or E, significantly increased renal-cortical glutathione content. Diabetic Neuropathy Alpha-lipoic acid has been studied extensively in Europe for the treatment of diabetic neuropathy.25-27 Three large-scale, double-blind, placebocontrolled trials have been conducted on the effect of ALA for neuropathy – the Alpha-Lipoic Acid in Diabetic Neuropathy (ALADIN) studies. The first ALADIN study (n=328 type 2 diabetics) found three weeks of IV ALA at 600 mg daily was superior to placebo for reducing symptoms of neuropathy.25 ALADIN II examined nerve conduction parameters in a two-year trial and found improvement in some nerve conduction parameters with ALA compared to placebo.26 In the seven-month ALADIN III trial, 509 subjects received either 600 mg IV ALA for three weeks, followed by 600 mg orally three times daily for six Alternative Medicine Review u Volume 11, Number 3 u 2006 Page 233 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006 Alpha-Lipoic Acid Monograph months; 600 mg IV ALA daily for three weeks, followed by placebo three times daily for six months; or double placebo. While no significant differences were noted in subjective symptom evaluation among the groups, treatment with ALA was associated with improvement in nerve function.27 In one randomized, double-blind, placebocontrolled study, known as the SYDNEY trial, 60 type 2 diabetic patients with diabetic sensorimotor polyneuropathy (DSPN) were administered 600 mg IV ALA daily, five days/week for a total of 14 treatments, while an equivalent number of DSPN patients were given placebo for the same duration. At the end of the trial, the ALA group reported significant improvement in overall symptoms (e.g., lancinating and burning pain, numbness, and tingling) compared to the placebo group (average decrease in total symptom score (TSS): 5.7 versus 1.8) (p<0.001).28 Another smaller study demonstrated similar results using oral ALA. In this trial, 24 type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to 600 mg ALA three times daily or placebo for three weeks. Neuropathic symptoms (pain, burning, paresthesia, and numbness) in the feet were scored regularly and summarized as a TSS. At the end of the trial the ALA group reported significant improvements in TSS compared to placebo (TSS decreases: 3.8 versus 1.9) (p=0.021).29 Lipid peroxidation is believed to play a role in the development of neuropathy. In an in vitro study, lipoic acid decreased lipid peroxidation of nerve tissue.30 ALA significantly reduced neuropathy symptoms in a group of 20 diabetics taking 600 mg daily for three months. It should be noted that two other groups of 20 each, receiving vitamin E or selenium, also experienced significant improvement compared to the control group.31 ALA may be beneficial for diabetic cardiac autonomic neuropathy (CAN). A four-month trial of oral ALA at a dose of 800 mg daily (n=39) or placebo (n=34) demonstrated a trend toward improvement in measurements of CAN in the treatment group.32 Cataracts The enzyme aldose reductase plays an important role in the development of cataracts in diabetes. Lipoic acid inhibited aldose reductase activity in the rat lens.15 In another animal study, ALA inhibPage 234 ited cataract formation experimentally induced by buthionine sulfoximine, an inhibitor of glutathione synthesis. ALA administration maintained levels of glutathione, ascorbic acid, and alpha-tocopherol in the lens.33 These same researchers found that R-ALA reached concentrations in rat lens two- to seven-fold higher than S-ALA, with the racemic mixture reaching levels between the two.34 Glaucoma Lipoic acid was administered to 75 subjects with open-angle glaucoma at dosages of either 75 mg daily for two months or 150 mg daily for one month. Thirty-one others served as controls and were given only local hypotensive therapy. The greatest improvements in the biochemical parameters of glaucoma and visual function were observed in the group receiving 150 mg lipoic acid.35 Ischemia-Reperfusion Injury After an area of tissue has been deprived of blood for a period of time, such as occurs in the brain after a stroke or in the heart after clot dissolution, reperfusion of the tissues causes a burst of free radical formation. Several animal studies have demonstrated the effectiveness of DHLA in the prevention of reperfusion injury.36-40 Animal studies support the efficacy of ALA as a neuroprotectant after ischemia.41,42 One week after ischemia injury and reperfusion in rats, the amplitude of sensory action potential and sensory conduction velocity was significantly improved with ALA.41 Amanita Mushroom Poisoning Alpha-lipoic acid infusions were used in the treatment of amanita mushroom poisoning in 75 patients between 1974 and 1978. Normally, up to 50 percent of patients recover without intervention; however, 89 percent (67 of 75) recovered after lipoic acid infusion.43 Alcoholic Liver Disease Although preliminary studies have indicated possible benefit of lipoic acid in the treatment of alcoholic liver disease, the only controlled, double-blind study found ALA had no significant influence on the course of the disease.44 Alternative Medicine Review u Volume 11, Number 3 u 2006 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006 Alpha-Lipoic Acid Monograph Cognitive Function Alpha-lipoic acid may have a positive effect on patients with Alzheimer’s disease and other types of memory dysfunction secondary to trauma or cerebral vascular accident. By decreasing oxidative damage in the central nervous system, ALA may decrease the severity of central nervous system disorders.2 An animal study has shown supplementation with lipoic acid improves long-term memory in aged mice; however, no effect in young mice was shown.45 This lack of treatment effect in young mice suggests ALA does not improve memory from a general standpoint; instead, it appears ALA compensates for agerelated memory deficits. Alpha-lipoic acid also appears to protect brain cells from the damaging effects of some hazardous chemicals. Researchers at the University of Rochester reported neuron damage from excess N-methyl-D-aspartate was prevented by lipoic acid.46 Another study found buthionine sulfoximine-stimulated neurotoxicity in rat brain was partially prevented by R-ALA, but not RS-ALA, S-ALA, or RS-DHLA.47 Heavy Metal Toxicity In vitro and animal studies suggest lipoic acid supplementation might be a beneficial component in the treatment of heavy metal toxicity, particularly toxicity involving lead, cadmium, mercury, or copper.2,48-53 In one study an intraperitoneal injection of 25 mg/kg ALA given to rats for seven days was able to significantly alter the oxidative stress induced by lead toxicity.48 Another study demonstrated ALA, at concentrations of 5 mM, was able to protect rat hepatocytes from cadmium toxicity (200 µM) by preventing decreases in total glutathione and increases in lipid peroxidation.49 Furthermore, a study on mercury intoxication revealed an injection of 10 mg/kg/day ALA in rats inoculated with 1 mg/kg/day mercuric chloride prevented damage to nerve tissue caused by lipid peroxidation.52 Long-Evans Cinnamon rats have a genetic defect that causes them to accumulate copper in the liver – in a manner similar to patients with Wilson’s disease – and spontaneously develop acute hepatitis. ALA has been shown to protect these rats from developing hepatitis.53 ALA appears to improve tissue redox status in metal toxicity and during chelation with dithiol compounds, including d imercaptosuccinic acid (DMSA).54 Anecdotal reports note the use of lipoic acid may improve the clearance of toxic metals. Other Indications Other therapeutic uses for ALA or DHLA include protection from radiation injury and prevention of HIV viral replication by inhibition of reverse transcriptase and nuclear factor kappa-B (a protein that functions as a nuclear transcription factor and appears to play a role in inflammation).55,56 Side Effects and Toxicity Alpha-lipoic acid appears to be safe in dosages generally prescribed clinically. The LD50 was 400-500 mg/kg after an oral dosage in dogs;2 however, lower dosages (20 mg/kg) given intraperitoneally to severely thiamine-deficient rats proved fatal. These adverse effects were prevented when thiamine was administered with lipoic acid.57 Anecdotal evidence suggests ALA may be hepatotoxic to cats at doses greater than 20 mg daily. There have not been sufficient studies to guarantee safe use in pregnancy. Allergic skin conditions are among the few reported side effects of lipoic acid administration in humans. Dosage Recommended oral therapeutic dosages of alpha-lipoic acid range from 600-1800 mg daily. Because R-lipoic acid is more efficiently absorbed and utilized by the body, R-ALA may be equally effective at lower doses. References 1. 2. 3. 4. Alternative Medicine Review u Volume 11, Number 3 u 2006 Carreau JP. Biosynthesis of lipoic acid via unsaturated fatty acids. Methods Enzymol 1979;62:152-158. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med 1995;19:227-250. Handelman GJ, Han D, Tritschler H, Packer L. Alpha-lipoic acid reduction by mammalian cells to the dithiol form and release into the culture medium. Biochem Pharmacol 1994;47:1725-1730. Bustamante J, Lodge JK, Marcocci L, et al. Alphalipoic acid in liver metabolism and disease. Free Radic Biol Med 1998;24;6:1023-1039. Page 235 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006 Alpha-Lipoic Acid 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Monograph Hermann R, Niebch G, Borbe HO, et al. Enantioselective pharmacokinetics and bioavailability of different racemic α-lipoic acid formulations in healthy volunteers. Eur J Pharm Sci 1996;4:167-174. Breithaupt-Grogler K, Niebch G, Schneider E, et al. Dose-proportionality of oral thioctic acid – coincidence of assessments via pooled plasma and individual data. Eur J Pharm Sci 1999;8:57-65. Scholich H, Murphy ME, Sies H. Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on alphatocopherol. Biochem Biophys Acta 1989;1001:256261. Busse E, Zimmer G, Schopohl B, Kornhuber B. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung 1992;42:829-831. Kagan V, Serbinova E, Packer L. Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling. Biochem Biophys Res Commun 1990;169:851-857. Sigel H, Prijs B, McCormick DB, Shih JC. Stability and structure of binary and ternary complexes of alpha-lipoate and lipoate derivatives with Mn2+, Cu2+, and Zn2+ in solution. Arch Biochem Biophys 1978;187:208-214. Grunert RR. The effect of DL alpha-lipoic acid on heavy-metal intoxication in mice and dogs. Arch Biochem Biophys 1960;86:190-194. Muller L, Menzel H. Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes. Biochim Biophys Acta 1990;1052:386-391. Keith RL, Setiarahardjo I, Fernando Q, et al. Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Toxicology 1997;116:67-75. Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 1997;99:457468. Ou P, Nourooz-Zadeh J, Tritschler HJ, Wolff S. Activation of aldose reductase in rat lens and metalion chelation by aldose reductase inhibitors and lipoic acid. Free Radic Res 1996;25:337-346. Kishi Y, Schmelzer JD, Yao JK, et al. Alpha-lipoic acid: effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy. Diabetes 1999;48;2045-2051. Heller B, Burkhart V, Lampeter E, Kolb H. Antioxidant therapy for the prevention of type 1 diabetes. Adv Pharmacol 1997;38:629-638. Estrada DE, Ewart HS, Tsakiridis T, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 1996;45:1798-1804. Page 236 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung 1995;45:872-874. Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin-stimulated glucosedisposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996;104:284-288. Konrad T, Vicini P, Kusterer K, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 1999;22:280-287. Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 1999;27:309-314. Streeper RS, Henriksen EJ, Jacob S, et al. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 1997;273:E185-E191. Melhem MF, Craven PA, Derubertis FR. Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus. J Am Soc Nephrol 2001;12:124-133. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38:14251433. Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebocontrolled trial (ALADIN II). Alpha Lipoic Acid In Diabetic Neuropathy. Free Radic Res 1999;31:171179. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. AlphaLipoic Acid in Diabetic Neuropathy. Diabetes Care 1999;22:1296-1301. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003;26:770-776. Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 1999;16:1040-1043. Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med 1996;21:631-639. Alternative Medicine Review u Volume 11, Number 3 u 2006 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006 Alpha-Lipoic Acid Monograph 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. Kahler W, Kuklinski B, Ruhlmann C, Plotz C. Diabetes mellitus – a free radical-associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med 1993;48:223232. [Article in German] Ziegler D, Schatz H, Contrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care 1997;20:369-373. Maitra I, Serbinova E, Tritschler H, Packer L. Alpha-lipoic acid prevents buthionine sulfoximineinduced cataract formation in newborn rats. Free Rad Biol Med 1995;18:823-829. Maitra I, Serbinova E, Tritschler HJ, Packer L. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun 1996;221:422429. Filina AA, Davydova NG, Endrikhovskii SN, Shamshinova AM. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 1995;111:6-8. [Article in Russian] Scheer B, Zimmer G. Dihydrolipoic acid prevents hypoxic/reoxygenation and peroxidative damage in rat mitochondria. Arch Biochem Biophys 1993;302:385-390. Assadnazari H, Zimmer G, Freisleben HJ, et al. Cardioprotective efficiency of dihydrolipoic acid in working rat hearts during hypoxia and reoxygenation. 31P nuclear magnetic resonance investigations. Arzneimittelforschung 1993;43:425432. Prehn JH, Karkoutly C, Nuglisch J, et al. Dihydrolipoate reduces neuronal injury after cerebral ischemia. J Cereb Blood Flow Metab 1992;12:78-87. Panigrahi M, Sadguna Y, Shivakumar BR, et al. Alpha-lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Brain Res 1996;717:184-188. Cao X, Phillis JW. The free radical scavenger, alpha-lipoic acid, protects against cerebral ischemia-reperfusion injury in gerbils. Free Rad Res 1995;23:365-370. Mitsui Y, Schmelzer JD, Zollman PJ, et al. Alphalipoic acid provides neuroprotection from ischemiareperfusion injury of peripheral nerve. J Neurol Sci 1999;163:11-16. Haramaki N, Assadnazari H, Zimmer G, et al. The influence of vitamin E and dihydrolipoic acid on cardiac energy and glutathione status under hypoxia-reoxygenation. Biochem Mol Biol Int 1995;37:591-597. Bartter FC, Berkson BM, Gallelli J, et al. Thioctic acid in the treatment of poisoning with alphaamanitin. In: Faulstich H, Kommerell B, Wieland T, eds. Amanita Toxins and Poisoning. Baden-Baden, Germany: Verlg Gerhard Witzstrock; 1980:197202. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. Alternative Medicine Review u Volume 11, Number 3 u 2006 Marshall AW, Graul RS, Morgan MY, Sherlock S. Treatment of alcohol-related liver disease with thioctic acid: a six month randomised double-blind trial. Gut 1982;23:1088-1093. Stoll S, Hartmann H, Cohen SA, Muller WE. The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits. Pharmacol Biochem Behav 1993;46:799-805. Greenamyre JT, Garcia-Osuna M, Greene JG. The endogenous cofactors, thioctic acid and dihydrolipoic acid, are neuroprotective against NMDA and malonic acid lesions of striatum. Neurosci Lett 1994;171:17-20. Lockhart B, Jones C, Cuisinier C, et al. Inhibition of L-homocysteic acid and buthionine sulphoximine-mediated neurotoxicity in rat embryonic neuronal cultures with alpha-lipoic acid enantiomers. Brain Res 2000;855:292-297. Gurer H, Ozgunes H, Oztezcan S, Ercal N. Antioxidant role of alpha-lipoic acid in lead toxicity. Free Radic Biol Med 1999;27:75-81. Muller L, Menzel H. Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes. Biochem Biophys Acta 1990;1052:386-391. Muller L. Protective effects of DL-alpha-lipoic acid on cadmium-induced deterioration of rat hepatocytes. Toxicology 1989;58:175-185. Sumathi R, Baskaran G, Varalakshmi P. Relationship between glutathione and DL alpha-lipoic acid against cadmium-induced hepatotoxicity. Jpn J Med Sci Biol 1996;49:39-48. Anuradha B, Varalakshmi P. Protective role of DLalpha-lipoic acid against mercury-induced neural lipid peroxidation. Pharmacol Res 1999;39:67-80. Yamamoto H, Watanabe T, Mizuno H, et al. The antioxidant effect of DL-alpha-lipoic acid on copper-induced acute hepatitis in Long-Evans Cinnamon (LEC) rats. Free Radic Res 2001;34:6980. Pande M, Flora SJ. Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats. Toxicology 2002;177:187-196. Baur A, Harrer T, Peukert M, et al. Alpha-lipoic acid is an effective inhibitor of human immunodeficiency virus (HIV-1) replication. Klin Wochenschr 1991;69:722-724. Suzuki YJ, Aggarwal BB, Packer L. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T-cells. Biochem Biophys Res Commun 1992;189:1709-1715. Gal EM. Reversal of selective toxicity of (-)-alphalipoic acid by thiamine in thiamine-deficient rats. Nature 1965;207:535. Page 237 Copyright © 2006 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 11, Number 3 September 2006